AB0103 THE CAUSAL ASSOCIATION BETWEEN MTOR-DEPENDENT CIRCULATING PROTEINS AND PSORIATIC ARTHRITIS: A MENDELIAN RANDOMIZATION STUDY
Authors: Z. Zhao, F. Liu, Z. Wang, S. Song, J. Qiao, S. X. Zhang, X. Li
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Psoriatic arthritis (PsA) is a chronic, immune-mediated arthropathy mainly affecting the peripheral joints, spine, and sacroiliac joints<sup>[1]</sup> The key pathologic outcomes of PsA are ‘uncontrolled proliferation’ of synovial fibroblasts (FLS), along with the proliferation of endothelial cells (EC) and T cells. Growing evidence found that the proliferation of these cells of psoriatic arthritis are dependent on the PI3K-AKT-mTOR kinase system.<sup>[2]</sup> <h3>Objectives</h3> This study aimed to investigate the causality between key mTOR kinase cascade proteins and psoriatic arthritis. <h3>Methods</h3> We used a 2-sample Mendelian randomization (MR) method to evaluate the causal effect of five mTOR-dependent circulating proteins on psoriatic arthritis. Data about mTOR-related gene exposure (eIF4A3, eIF4E2, eIF4E-BP2, eIF4G3, RP-S6KA) in plasma were obtained from the publicly available proteomics-GWAS INTEVAL study (https://www.phpc.cam.ac.uk/ceu/proteins/), which included 3,622 plasma protein assays from 3,301 participants. PsA relative single nucleotide polymorphisms (SNPs) were obtained from the FinnGen study(https://r5.finngen.fi/). 1637 cases and 212242 controls of European descent were included in our study. Effect estimates were evaluated using inverse-variance weighted method. There are also other MR analyses, including MR-Egger regression, and the weighted median methods. Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) test, Cochran’s Q test, and MR-Egger regression were performed in sensitivity analyses. All statistical analyses were performed in R (version 4.0.3). <h3>Results</h3> Five proteins were extracted from the downstream target of mTOR, which were eIF4A3 eIF4E2, eIF4E-BP2, eIF4G3 and RP-S6KA. Subsequently, 15, 9, 10, 16, and 18 IVs with mTOR significantly associated with psoriatic arthritis were extracted from genome-wide association studies (P&lt;5x10<sup>-6</sup>). F statistics of all the selected IVs are greater than 10, indicating that all IVs were strongly correlated with exposure. After the removal of SNPs with high linkage disequilibrium and palindrome, the final 8,13,10,7, and 13 SNPs were used as final instrument variables for them, respectively. Evidence for an effect of eIF4E2 on PsA risk was found in inverse-variance weighted method (OR=0.844; 95%CI,0.735,0.969; p=0.016) and weighted median (OR=0.819; 95%CI,0.687,0.977 P=0.026) using 13 single nucleotide polymorphisms (SNPs) as the instruments. For the other four common mTOR related targets, we have not found a causal relationship between them and PsA including eIF4A3 (IVW: OR = 0.912;95% CI,0.749,1.111; p = 0.359), eIF4E-BP2 (IVW: OR = 0.842; 95% CI,0.788,1.031; p = 0.075), eIF4G3 (IVW: OR = 0.768;95% CI,0.709,1.135; p = 0.366) and RP-S6KA (IVW: OR = 0.893; 95% CI, 0.767,1.040; p = 0.146). To verify the robustness of our model, we performed sensitivity analysis. No potential heterogeneity was found by Cochran’s Q test (Q=6.311; p=0.852). MR-Egger regression (P=0.425, intercept=0.038) found no horizontal pleiotropy. Similarly, the result of MR-PRESSO test found no evidence of horizontal pleiotropy. In addition, no SNP was identified as an obvious factor affecting the association in the leave-one-out analysis. (Figure 1) <h3>Conclusion</h3> In summary, this 2-sample mendelian randomization study found a causal protective association of eIF4E2 with psoriatic arthritis. This novel result provides the scope to develop new therapeutics targeting PI3K/Akt/mTOR signaling pathway in psoriatic arthritis. <h3>References</h3> [1]Umezawa Y. Psoriatic arthritis. J Dermatol. 2021;48(6):741-749. [2]Raychaudhuri SK, Raychaudhuri SP. mTOR Signaling Cascade in Psoriatic Disease: Double Kinase mTOR Inhibitor a Novel Therapeutic Target. Indian J Dermatol. 2014;59(1):67-70. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.